AZOPT 10mg / ml ophthalmic drops suspension medication leaflet

AZOPT 10 mg/ml eye drops, suspension

Each ml of suspension contains 10 mg brinzolamide.

Each ml of suspension contains 0.1 mg benzalkonium chloride.

For a full list of excipients, see section 6.1.

Eye drops, suspension.

White to off-white suspension.

AZOPT is indicated to decrease elevated intraocular pressure in:

* ocular hypertension

* open-angle glaucomaas monotherapy in adult patients unresponsive to beta-blockers or in adult patients in whom beta-blockers are contraindicated, or as adjunctive therapy to beta-blockers or prostaglandin analogues (seealso section 5.1).

When used as monotherapy or adjunctive therapy, the dose is one drop of AZOPT in the conjunctivalsac of the affected eye(s) twice daily. Some patients may have a better response with one dropthree times a day.

No dose adjustment in elderly patients is necessary.

AZOPT has not been studied in patients with hepatic impairment and is therefore not recommended insuch patients.

AZOPT has not been studied in patients with severe renal impairment (creatinine clearance< 30 ml/min) or in patients with hyperchloraemic acidosis. Since brinzolamide and its main metaboliteare excreted predominantly by the kidney, AZOPT is therefore contra-indicated in such patients (seealso section 4.3).

The safety and efficacy of AZOPT in infants, children and adolescents aged 0 to 17 years have notbeen established. Currently available data are described in sections 4.8 and 5.1. AZOPT is notrecommended for use in infants, children and adolescents.

For ocular use.

Nasolacrimal occlusion or gently closing the eyelid after instillation is recommended. This may reducethe systemic absorption of medicinal products administered via the ocular route and result in adecrease in systemic side effects.

Instruct the patient to shake the bottle well before use. After the cap is removed, if tamper evident snapcollar is loose, remove before using the product.

To prevent contamination of the dropper tip and suspension, care must be taken not to touch theeyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Instruct patients to keepthe bottle tightly closed when not in use.

When substituting another ophthalmic antiglaucoma agent with AZOPT, discontinue the other agentand start the following day with AZOPT.

If more than one topical ophthalmic medicinal product is being used, the medicines must beadministered at least 5 minutes apart. Eye ointments should be administered last.

If a dose is missed, treatment should be continued with the next dose as planned. The dose should notexceed one drop in the affected eye(s) three times daily.

* Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

* Known hypersensitivity to sulphonamides (see also section 4.4).

* Severe renal impairment.

* Hyperchloraemic acidosis.

AZOPT is a sulphonamide inhibitor of carbonic anhydrase and, although administered topically, isabsorbed systemically. The same types of adverse drug reactions that are attributable to sulphonamidesmay occur with topical administration, including Stevens-Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN). At the time of prescription, patients should be advised of the signs andsymptoms and monitored closely for skin reactions. If signs of serious reactions or hypersensitivityoccur, AZOPT should be withdrawn immediately.

Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. Use with cautionin patients with risk of renal impairment because the possible risk of metabolic acidosis (seesection 4.2).

Brinzolamide has not been studied in pre-term infants (less than 36 weeks gestational age) or thoseless than 1 week of age. Patients with significant renal tubular immaturity or abnormalities should onlyreceive brinzolamide after careful consideration of the risk benefit balance because of the possible riskof metabolic acidosis.

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertnessand/or physical coordination. AZOPT is absorbed systemically and therefore this may occur withtopical administration.

Concomitant therapy

There is a potential for an additive effect on the known systemic effects of carbonic anhydraseinhibition in patients receiving an oral carbonic anhydrase inhibitor and AZOPT. The concomitantadministration of AZOPT and oral carbonic anhydrase inhibitors has not been studied and is notrecommended (see also section 4.5).

AZOPT was primarily evaluated in concomitant administration with timolol during adjunctiveglaucoma therapy. Additionally the IOP-reducing effect of AZOPT as adjunctive therapy to theprostaglandin analogue travoprost has been studied. No long term data are available on the use of

AZOPT as adjunctive therapy to travoprost(see also section 5.1).

There is limited experience with AZOPT in the treatment of patients with pseudoexfoliative glaucomaor pigmentary glaucoma. Caution should be used in treating these patients and close monitoring ofintraocular pressure (IOP) is recommended. AZOPT has not been studied in patients with narrow-angle glaucoma and its use is not recommended in these patients.

The possible role of brinzolamide on corneal endothelial function has not been investigated in patientswith compromised corneas (particularly in patients with low endothelial cell count). Specifically,patients wearing contact lenses have not been studied and careful monitoring of these patients whenusing brinzolamide is recommended, since carbonic anhydrase inhibitors may affect corneal hydrationand wearing contact lenses might increase the risk for the cornea. Careful monitoring of patients withcompromised corneas such as patients with diabetes mellitus or corneal dystrophies is recommended.

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has beenreported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since AZOPT containsbenzalkonium chloride, close monitoring is required with frequent or prolonged use in dry eyepatients, or in conditions where the cornea is compromised.

AZOPT has not been studied in patients wearing contact lenses. AZOPT contains benzalkoniumchloride which may cause eye irritation and is known to discolour soft contact lenses. Contact withsoft contact lenses is to be avoided. Patients must be instructed to remove contact lenses prior to theapplication of AZOPT and wait at least 15 minutes after instillation of the dose before reinsertion.

Potential rebound effects following cessation of treatment with AZOPT have not been studied; the

IOP-lowering effect is expected to last for 5-7 days.

The safety and efficacy of AZOPT in infants, children and adolescents aged 0 to 17 years have notbeen established and its use is not recommended in infants, children or adolescents

Specific interaction studies with other medicinal products have not been performed with AZOPT.

In clinical studies, AZOPT was used concomitantly with prostaglandin analogues and timololophthalmic preparations without evidence of adverse interactions. Association between AZOPT andmiotics or adrenergic agonists has not been evaluated during adjunctive glaucoma therapy.

AZOPT is a carbonic anhydrase inhibitor and, although administered topically, is absorbedsystemically. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. Thepotential for interactions must be considered in patients receiving AZOPT.

The cytochrome P-450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main),

CYP2A6, CYP2C8 and CYP2C9. It is expected that inhibitors of CYP3A4 such as ketoconazole,itraconazole, clotrimazole, ritonavir and troleandomycin will inhibit the metabolism of brinzolamideby CYP3A4. Caution is advised if CYP3A4 inhibitors are given concomitantly. However,accumulation of brinzolamide is unlikely as renal elimination is the major route. Brinzolamide is notan inhibitor of cytochrome P-450 isozymes.

There are no or limited amount of data from the use of ophthalmic brinzolamide in pregnant women.

Studies in animals have shown reproductive toxicity following systemic administration (see alsosection 5.3).

AZOPT is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether brinzolamide/metabolites are excreted in human milk following topical ocularadministration. Animal studies have shown the excretion of minimal levels of brinzolamide in breastmilk following oral administration.

A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinuebreast-feeding or to discontinue/abstain from AZOPT therapy taking in to account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

Animal studies with brinzolamide demonstrated no effect on fertility. Studies have not been performedto evaluate the effect of topical ocular administration of brinzolamide on human fertility.

AZOPT has a minor influence on the ability to drive and use machines.

Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines(see also section 4.8). If blurred vision occurs at instillation, the patient must wait until the visionclears before driving or using machines.

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertnessand/or physical coordination (see also section 4.4 and section 4.8).

In clinical studies involving 2 732 patients treated with AZOPT as monotherapy or adjunctive therapyto timolol maleate 5 mg/ml, the most frequently reported treatment-related adverse reactions were:

dysgeusia (6.0%) (bitter or unusual taste, see description below) and temporary blurred vision (5.4%)upon instillation, lasting from a few seconds to a few minutes (see also section 4.7).

The following adverse reactions have been reported with brinzolamide 10mg/ml eye drops, suspensionand are classified according to the following convention: very common (≥1/10), common (≥1/100 to<1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), or notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness. The adverse reactions were obtained fromclinical trials and post-marketing spontaneous reports.

System Organ Classification MedDRA Preferred Term (v.15.1)

Infections and infestations Uncommon: nasopharyngitis, pharyngitis, sinusitis

Not Known: rhinitis

Blood and lymphatic system Uncommon: red blood cell count decreased, blood chloridedisorders increased

Immune system disorders Not Known: hypersensitivity

Metabolism and nutrition disorders Not known: decreased appetite

Psychiatric disorders Uncommon: apathy, depression, depressed mood, libidodecreased, nightmare, nervousness

Rare: insomnia

Nervous system disorders Uncommon: motor dysfunction, amnesia, dizziness,paraesthesia, headache

Rare: memory impairment, somnolence

Not Known: tremor, hypoaesthesia, ageusia

Eye disorders Common: blurred vision, eye irritation, eye pain, foreignbody sensation in eyes, ocular hyperaemia

Uncommon: corneal erosion, keratitis, punctate keratitis,keratopathy, deposit eye, corneal staining, corneal epitheliumdefect, corneal epithelium disorder, blepharitis, eye pruritus,conjunctivitis, eye swelling, meibomianitis, glare,photophobiadry eye, allergic conjunctivitis, pterygium,scleral pigmentation, asthenopia, ocular discomfort,abnormal sensation in eye, keratoconjunctivitis sicca,subconjunctival cyst, conjunctival hyperaemia, eyelidspruritus, eye discharge, eyelid margin crusting, lacrimationincreased

Rare: corneal oedema, diplopia, visual acuity reduced,photopsia, hypoaesthesia eye, periorbital oedema, intraocularpressure increased, optic nerve cup/disc ratio increased

Not Known: corneal disorder, visual disturbance, eye allergy,madarosis, eyelid disorder, erythema of eyelid

Ear and labyrinth disorders Rare: tinnitus

Not Known: vertigo

Cardiac disorders Uncommon: cardio-respiratory distress, bradycardia,palpitations

Rare: angina pectoris, heart rate irregular

Not Known: arrhythmia, tachycardia, hypertension, bloodpressure increased, blood pressure decreased, heart rateincreased

Respiratory, thoracic and Uncommon: dyspnoea, epistaxis, oropharyngeal pain,mediastinal disorders pharyngolaryngeal pain, throat irritation, upper airway coughsyndrome, rhinorrhoea, sneezing

Rare: bronchial hyperreactivity, upper respiratory tractcongestion, sinus congestion, nasal congestion, cough, nasaldryness

Not Known: asthma

Gastrointestinal disorders Common: dysgeusia

Uncommon: oesophagitis, diarrhoea, nausea, vomiting,dyspepsia, upper abdominal pain, abdominal discomfort,stomach discomfort, flatulence, frequent bowel movements,gastrointestinal disorder, hypoaesthesia oral, paraesthesiaoral, dry mouth

Hepato-biliary disorders Not Known: liver function test abnormal

Skin and subcutaneous tissue Uncommon: rash, rash maculo-papular, skin tightnessdisorders Rare: urticaria, alopecia, pruritus generalised

Not Known: Stevens-Johnson syndrome (SJS)/toxicepidermal necrolysis (TEN) (see section 4.4), dermatitis,erythema

Musculoskeletal and connective Uncommon: back pain, muscle spasms, myalgiatissue disorders Not Known: arthralgia, pain in extremity

Renal and urinary disorders Uncommon: renal pain

Not Known: pollakiuria

Reproductive system and breast Uncommon: erectile dysfunctiondisorders

General disorders and Uncommon: pain, chest discomfort, fatigue, feelingadministration site conditions abnormal

Rare: chest pain, feeling jittery, asthenia, irritability

Not Known: peripheral oedema, malaise

Injury, poisoning and procedural Uncommon: foreign body in eyecomplications

Description of selected adverse events

Dysgeusia (bitter or unusual taste in the mouth following instillation) was the most frequently reportedsystemic adverse reaction associated with the use of AZOPT during clinical studies. It is likely causedby passage of the eye drops in the nasopharynx via the nasolacrimal canal. Nasolacrimal occlusion orgently closing the eyelid after instillation may help reduce the incidence of this effect (see alsosection 4.2).

AZOPT is a sulphonamide inhibitor of carbonic anhydrase with systemic absorption. Gastrointestinal,nervous system, haematological, renal and metabolic effects are generally associated with systemiccarbonic anhydrase inhibitors. The same type of adverse reactions that are attributable to oral carbonicanhydrase inhibitors may occur with topical administration.

No unexpected adverse reactions have been observed with AZOPT when used as adjunctive therapy totravoprost. The adverse reactions seen with the adjunctive therapy have been observed with eachactive substance alone.

In small short-term clinical trials, approximately 12.5% of paediatric patients were observed toexperience adverse reactions, the majority of which were local, non-serious ocular reactions such asconjunctival hyperaemia, eye irritation, eye discharge, and lacrimation increased (see also section 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported.

Treatment should be symptomatic and supportive. Electrolyte imbalance, development of an acidoticstate, and possible nervous system effects may occur. Serum electrolyte levels (particularly potassium)and blood pH levels must be monitored.

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, carbonic anhydrase inhibitors,

ATC code: S01EC04

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye. Carbonicanhydrase catalyses the reversible reaction involving the hydration of carbon dioxide and thedehydration of carbonic acid.

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humoursecretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction insodium and fluid transport. The result is a reduction in intraocular pressure (IOP) which is a major riskfactor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Brinzolamide, aninhibitor of carbonic anhydrase II (CA-II), the predominant iso-enzyme in the eye, with an in vitro

IC50 of 3.2 nM and a Ki of 0.13 nM against CA-II.

The IOP-reducing effect of AZOPT as adjunctive therapy to the prostaglandin analogue travoprostwas studied. Following a 4 week run-in with travoprost, patients with an IOP ≥19 mmHg wererandomized to receive added treatment with brinzolamide or timolol. An additional decrease in meandiurnal IOP of 3.2 to 3.4 mmHg for the brinzolamide group and 3.2 to 4.2 mmHg for the timolol groupwere observed. There was an overall higher incidence of non-serious ocular adverse reactions, mainlyrelated to signs of local irritation, in the brinzolamide/travoprost groups. The events were mild and didnot affect the overall discontinuation rates in the studies (see also section 4.8).

A clinical trial was conducted with AZOPT in 32 paediatric patients less than 6 years of age,diagnosed with glaucoma or ocular hypertension. Some patients were naive to IOP therapy whilstothers were on other IOP-lowering medicinal product(s). Those who had been on previous IOPmedicinal product(s) were not required to discontinue their IOP medicinal product(s) until initiation ofmonotherapy with AZOPT.

Among patients who were naive to IOP therapy (10 patients), the efficacy of AZOPT was similar tothat seen previously in adults, with mean IOP reductions from baseline ranging up to 5 mmHg. Amongpatients who were on topical IOP-lowering medicinal product(s) (22 patients), mean IOP increasedslightly from baseline in the AZOPT group.

Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due toits high affinity for CA-II, brinzolamide distributes extensively into the red blood cells (RBCs) andexhibits a long half-life in whole blood (mean of approximately 24 weeks). In humans, the metabolite

N-desethylbrinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolitebinds mainly to CA-I in the presence of brinzolamide. In plasma, both brinzolamide and N-desethylbrinzolamide concentrations are low and generally below assay quantitation limits(<7.5 ng/ml).

Binding to plasma proteins is not extensive (about 60%). Brinzolamide is eliminated primarily byrenal excretion (approximately 60%). About 20% of the dose has been accounted for in urine asmetabolite. Brinzolamide and N-desethylbrinzolamide are the predominant components in the urinealong with trace levels (<1%) of the N-desmethoxypropyl and O-desmethyl metabolites.

In an oral pharmacokinetic study, healthy volunteers received 1 mg capsules of brinzolamide twicedaily for up to 32 weeks and RBC CA activity was measured to assess the degree of systemic CAinhibition.

Brinzolamide saturation of RBC CA-II was achieved within 4 weeks (RBC concentrations ofapproximately 20 µM). N-Desethylbrinzolamide accumulated in RBCs to steady state within 20-28 weeks reaching concentrations ranging from 6-30 µM. The inhibition of total RBC CA activity atsteady state was approximately 70-75%.

Subjects with moderate renal impairment (creatinine clearance of 30-60 ml/minute) were administered1 mg of brinzolamide twice daily orally for up to 54 weeks. Brinzolamide RBC concentration rangedfrom about 20 to 40 µM by week 4 of treatment. At steady-state, brinzolamide and its metabolite RBCconcentrations ranged from 22.0 to 46.1 and 17.1 to 88.6 µM, respectively.

N-desethylbrinzolamide RBC concentrations increased and total RBC CA activity decreased withdecreasing creatinine clearance but brinzolamide RBC concentrations and CA-II activity remainedunchanged. In subjects with the highest degree of renal impairment inhibition of total CA activity wasgreater although it was inferior to 90% at steady-state.

In a topical ocular study, at steady-state, brinzolamide RBC concentrations were similar to those foundin the oral study, but levels of N-desethylbrinzolamide were lower. Carbonic anhydrase activity wasapproximately 40-70% of predose levels.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single dose toxicity, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Developmental toxicity studies in rabbits with oral doses of brinzolamide of up to 6 mg/kg/day(125 times the recommended human ophthalmic dose) revealed no effect on foetal developmentdespite significant maternal toxicity. Similar studies in rats resulted in slightly reduced ossification ofskull and sternebrae of foetuses of dams receiving brinzolamide at doses of 18 mg/kg/day (375 timesthe recommended human ophthalmic dose), but not 6 mg/kg/day. These findings occurred at doses thatcaused metabolic acidosis with decreased body weight gain in dams and decreased foetal weights.

Dose-related decreases in foetal weights were observed in pups of dams receiving brinzolamide orallyranging from a slight decrease (about 5-6%) at 2 mg/kg/day to nearly 14% at 18 mg/kg/day. Duringlactation, the no adverse effect level in the offspring was 5 mg/kg/day.

Mannitol (E421)

Carbomer 974P

Tyloxapol

Edetate disodium

Sodium chloride

Hydrochloric acid/sodium hydroxide (to adjust pH)

Purified water

Not applicable.

2 years.

4 weeks after first opening.

This medicinal product does not require any special storage conditions.

5 and 10 ml opaque low density polyethylene bottles with polypropylene screw caps.

The following pack sizes are available: outer cartons containing 1 x 5 ml, 3 x 5 ml and 1 x 10 mlbottles. Not all pack sizes may be marketed.

No special requirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/00/129/001-3

Date of first authorisation: 9 March 2000

Date of latest renewal: 29 January 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu